MXPA04000649A

MXPA04000649A - Process.

Info

Publication number: MXPA04000649A
Application number: MXPA04000649A
Authority: MX
Inventors: Cid Pau
Original assignee: Adir
Priority date: 2001-07-24
Filing date: 2002-07-23
Publication date: 2004-10-27
Also published as: DK1279665T3; SI1279665T1; PL355161A1; ATE386717T1; US20040248814A1; KR100694528B1; CN100503568C; HU0202414D0; EA200400129A1; KR20040029378A; EP1279665B1; PT1279665E; JP4083118B2; AR036187A1; AU2002328954B2; HUP0202414A3; JP2005501829A; EA007000B1; CY1107403T1; EP1279665A2

Abstract

A process for the preparation of a compound of formula (IV), or an ester or a salt thereof comprising 1) reacting a compound of formula (I), (wherein Ra represents C1-4 alkyl, Rb represents C1-4 alkyl and Rc represents C1-6 alkyl) with a compound of formula X2C=0 (wherein each X independently represents a leaving group) to give a compound of formula (II), (wherein Ra, Rb and Rc are as hereinbefore defined); and 2) reacting said compound of formula (II) with a compound of formula (III), (wherein Rd represents hydrogen or a protecting group).

Description

PROCESS FOR PREPARATION OF PERINDOPRIL, ITS ANALOGUE COMPOUNDS AND SALTS THEREOF USING 2, 5-DIOXO-OXAZOLIDINE INTERMEDIATE COMPOUNDS DESCRIPTION OF THE INVENTION This invention relates to a new process for the preparation of perindopril of (2S; 3aS, 7aS) -1- [(S) -N- [(S) -1-carboxybutyl] alanyl 1-ethylester. ] hexahydro-2-indoline carboxylic acid and analogs and salts thereof, especially tert-butylamine salts. Perindopril and its perindopril erbumine of tert-butylamine salt are used as inhibitors of the enzyme that converts angiotensin (ECA).

Perindopril Perindopril acts as a prodrug of diacid perindoprilat, its active form. After oral administration perindopril is rapidly absorbed and extensively metabolized, mainly in the liver, to perindoprilat and inactive metabolites including glucuronides. Perindopril is used in the treatment of REF: 153369 hypertension and heart failure since the inhibitors of the enzyme that converts angiotensin inhibits the conversion of angiotensin I to angiotensin II. There are anti-hypertensive agents that act as vasodilators and reduce peripheral resistance; they have beneficial effects on left ventricular dysfunction and reduce protein urea associated with kidney diseases. Other areas of potential therapy have been reported, including myocardial infarction and diabetic nephropathy, although adverse effects include hypotension, rashes on the skin (rash), angioedema, cough, taste alterations, impaired renal function and hyperkalemia. Perindopril synthesized first by a process described in ?? -? - 00496658. Today, perindopril is conventionally prepared by the processes described in detail below. The first process is a four-step process starting from a perhydroindol-carboxylic acid that must first be protected before the reaction is carried out. The side chain N is then prepared as shown in Reaction Scheme 1 by coupling a suitably protected perhydroindole carboxylic acid with a reactive derivative of a pure enantiomeric amino acid such as alanine. The rest of the side chain is formed by reductive amination, conventionally achieved using a metal hydride such as sodium cyanoborohydride. The deprotection is then carried out. REACTION SCHEME 1 Including both the protective and the deprotection stages of carboxy, this synthetic route for perindopril comprises four stages and the reductive amination step leads to the formation of two possible stereoisomers which have to be separated. Therefore, to produce an enantiomerically pure drug, a difficult separation procedure needs to be conducted once the current perindopril has been prepared. An alternative method for preparing perindopril is described in Reaction Scheme 2 and this involves coupling a preformed side chain with the protected perhydroindole carboxylic acid class, such as dicyclohexylcarbodiimide (DCC). By including again both the protection and deprotection stages, this method requires three stages. REACTION SCHEME 2 It should be noted that in both the synthesis of the final stage involves the deprotection of the carboxylate group bound to the perhydroindole, usually carried out by catalytic hydrogenation (for example, when the protecting group is a benzyl class) or under acidic conditions (for example when the group protector is a class of tert-butyl). In addition, the deprotection step can cause epimerization of some of the stereocenters in the molecule. The inventors have invented a new process for the preparation of perindopril and analogs and salts thereof which involve only two simple steps and does not require the problematic use of protecting groups. In addition, the synthesis gives rise to enantiomerically pure products without the need for any of the stereoisomer separation processes. The process involves the use of a class of oxazolidine that is subsequently opened to form perindopril or analogs thereof.

The only by-product in this coupling reaction is C02 and the process avoids the use of coupling agents such as DCC and the corresponding formation of problematic by-products such as dicyclohexylurea which is notoriously difficult to remove from a reaction mixture. Thus, the perspective from one aspect of the invention provides a process for the preparation of a compound of formula (IV) or an ester or a salt thereof comprising: 1) reacting a compound of formula (I) wherein Ra represents Ci_4i alkyl represents C y alkyl and R c represents Ca-6 alkyl with a compound of formula X 2 C = 0 (wherein each X independently represents a leaving group) to give a compound of formula (II) wherein Ra, Rb and Rc are as defined above; and 2) reacting the compound of formula (II) with a compound of formula wherein R 'represents hydrogen or a protecting group. In the compound of formula (I), Ra is preferably methyl or especially ethyl. Rb is preferably ethyl or especially methyl. Rc is preferably ethyl or butyl but especially propyl. It is also preferred if the stereochemistry of the two stereocenters in the compounds of formula (I) are (S). The compound of formula (I) is therefore most preferably a compound of formula (A) The compounds of formula (I) can be prepared by techniques known in the art. For example, a compound of formula (A) can be prepared from the reaction of an alanine optionally protected with a suitably functionalized pentanoic acid ester. Alternatively, the compounds of formula (I) can be prepared as shown in the reaction scheme below: wherein Ra, Rb and Rc are as defined above and Re together with the oxygen atom to which they are attached form a leaving group , for example -OS02CF3. The preferences for Ra / ¾ and Rc are as described above. The compound of formula (VI) can be prepared from D-lactic acid by conventional processes. The stereochemistry of the compound of formula (V) is preferably (S) to allow the preparation of a compound of formula (A). The deprotection of the carboxyl group is carried out by hydrogenation. This reaction forms yet another aspect of the invention. The compound of formula (I) is reacted with a compound capable of introducing a carbonyl group to allow the formation of oxazolidine. A comprehensive discussion of the synthesis of oxazolidines (also referred to as amino acid-N-carboxy anhydrides) can be found in the book "a-Amino Acid-N-carboxy anhydrides and related heterocycles, synthesis, properties, peptide synthesis, polymerization (oc- Aminoacid-N-carboxy anhydrides and related heterocycles, syntheses, properties, peptide synthesis, polymerisation) of Hans Rytger Kricheldorf (Springer-Verlag, Berlin 1987) which is incorporated herein by reference. In this way, the oxazolidine ring can be formed by the Fuchs-Farthing method as described herein. The Fuchs-Farthing method involves the direct reaction of free amino acids with phosgene, the process of the reaction which, by means of an N-chloro-formyl amino acid intermediate, is converted to the anhydride in the presence of hydrochloric acid. Suitable compounds capable of introducing a carbonyl group are of formula X 2 C = 0. Each X independently can be any suitable leaving group, which are well known in the art. In this way, each X must be able to be displaced by means of the unique nucleophilic pairs present in the oxygen and nitrogen atoms of the compound (I). For example, X can be a halogen, tosylate, mesylate, alkoxy group, alkylthio or imidazolyl group. In general, when X forms an ester or thioester bond with the CO part, a suitable compound will be found to introduce a carbonyl, for example (Cl 3 CO) -. In a preferred embodiment both X are the same and in still another preferred embodiment both X represent halogen, preferably chlorine. In this example, the compound of formula X2C = 0 is, of course, phosgene (C12C = 0). Since phosgene is dangerous to handle, it may be preferable to use it in its less active form, triphosgene ((CCl 30) 2CO.In another preferred embodiment, X 2 C = 0 is α, β'-carbonyldiimidazole. The nucleophilic nitrogen and oxygen atoms in the compound of formula (I) attack the electrophilic class X2C = 0 allowing a 5-endo-trig cyclization to occur.Depending on the nature of the X2CO group, this reaction can be carried out in a variety of solvents. low boiling, very inert are useful as reaction media, for example tetrahydrofuran, dioxane, dichloromethane.When the carbonyl introducing agent is triphosgene or phosgene, the skilled chemist will appreciate that careful control over the reaction, is required to avoid potentially dangerous conditions For example, the reaction can be carried out in a water / dichloromethane mixture in the presence of sodium monoacid phosphate. In formula (II), it may be necessary to neutralize any agent that introduces residual carbonyl, for example, by adding a base such as pyridine. The compound of formula (II) can then be isolated using processing techniques and washing phases. The conversion through the compound (II) can be achieved in yields in excess of 70%, for example 80% without any loss of the stereochemistry. In a preferred embodiment, the compound of formula (II) is of formula (B) Compounds of formula (II), especially the compound of formula (B) are new and form a further aspect of the invention. Therefore, in view of a further aspect, the invention provides a compound of formula (II) as described above. The compound (II) is then contacted with a compound of formula (III). In the compounds of formula (III), Rd is preferably a hydrogen atom, however it may represent a protecting group such as benzyl. Compounds of formula (III) have been described in the literature and their preparation is described, inter alia, in EP-A-0037231. This reaction can be carried out in a suitable organic solvent, for example dichloromethane in the presence of a weak base, for example, triethylamine. The preferred compound of formula (III) is of formula (C): that is to say (2S, 3aS, 7aS) -2-carboxyperhydroindol. The product of the reaction of the compounds of the formulas (B) and (C) is, of course, perindopril which can be purified by conventional techniques or immediately crystallized as a salt, for example a salt of tert-buty1amin. After the reaction of the compounds (II) and (III), and if deprotection of the perhydroindolcarboxylic acid is necessary, the isolation of the product can be carried out. In this regard, water is added to the reaction mixture and the mixture is cooled to 15 ° C. The pH of the mixture can be adjusted to about 4.2 by the addition of acid, for example hydrochloric acid, and the aqueous phase is extracted with dichloromethane. The organic extract can then be dried under reduced pressure below 40 ° C to provide an oil. The reaction of the compounds (II) and (III) can be carried out without isolation of the compound of the formula (II) from the original medium. This can be converted to the tert-butylamine salt (for example perindopril erbumine) simply by contacting the oil in an appropriate solvent with tert-butylamine. After isolation, the salt can be isolated in an excess of 70% yield. The perindopril or derivative thereof produced by the process of the invention can be used in the indications discussed in the preceding section of the text and in the indications known to the skilled person. Perindopril or derivatives thereof can be formulated as part of a pharmaceutical composition and administered by any standard routes such as oral, transmucosal or by injection. The invention will now be further described in connection with the following non-limiting Examples. Example 1 2, 5-dioxo-3- [1- (S) -ethoxycarbonyl-butyl] -4- (S) -methyl-oxazolidine A solution of 28.7 g of sodium monoacid phosphate in 200 mL of water was prepared and heated at 30-35 ° C. After the dissolution was complete, the mixture was cooled to room temperature and charged with 160 mL of dichloromethane. 20 g of N- [1- (S) -ethoxycarbonyl-butyl] - (S) -alanine was added to the well-stirred mixture, and the resulting mixture was cooled to 15 ° C. A solution of 10.9 g of triphosgene in 400 mL of dichloromethane was slowly added for 30 minutes keeping the temperature at or above 20 ° C.

After the addition of triphosgene, the mixture was stirred for 30 minutes and 0.1 ml of pyridine was added to destroy the residual phosgene. After stirring for an additional 1 hour, or until the phosgene was completely destroyed, the phases were separated and the organic phase was washed first with 100 mL of 2N HC1 and then with 10 mL of water. The organic phase was filtered and the solvent was evaporated under reduced pressure. 18.85 g of a pale yellow oil was obtained. Assay: 95% (of 2,5-dioxo-3- [1- (S) -ethoxycarbonyl-butyl] -4- (S) -methyl-oxazolidine). Yield: 80% Example 2 (2S, 3aS, 7aS) -1-. { 2- [1-ethoxycarbonyl) - (S) -butylamino] - (S) -propionyl} -octahydroindol-2-carboxylate of tert-butylamine (PERINDOPRIL ERBUMIN) 20 g of (2S, 3aS, 7aS) -2 -carboxy-octahydroindole were suspended in 150 mL of dichloromethane at 25 ° C and 16.5 mL of triethylamine was added. A solution of 27.5 g of 2 was added slowly, 5-dioxo-3- [1- (S) -ethoxycarbonyl-butyl] -4- (S) -methyl-oxazolidine (Example 1) in 40 mL of dichloromethane for 3 hours and the mixture was stirred for an additional 1 hour. 150 mL of water was added and the biphasic mixture was cooled to 15 ° C. The pH was adjusted to 4.2 by the addition of 2N hydrochloric acid ("52 mL" was required). The organic phase was separated and the aqueous phase was extracted with 100 mL of dichloromethane. The organic extracts were combined and filtered and the solvent was evaporated under reduced pressure keeping the temperature below 40 ° C to obtain an oil. 100 mL of acetonitrile was added to the oil and the solvent was then removed in vacuo. The resulting oil was dissolved in 300 mL of acetonitrile and the solution was heated to 35 ° C. A solution of 12.5 mL of tert-butylamine in 50 mL of acetonitrile was added slowly over 30 minutes and the resulting mixture was stirred at 40 ° C for 1 hour. The mixture was cooled and stirred at 5 ° C for an additional 1 hour. The resulting precipitate was filtered and washed with 50 ml of acetonitrile twice. 78.27 g of moist white solid were obtained (42.34 g of dry product calculated by loss in dryness). 70.27 g of wet solid were suspended in 160 mL of acetonitrile and 4.75 mL of water was added. The mixture was stirred at 40 ° C for 1 hour before being cooled and stirred at 5 ° C for 1 hour. The solid was filtered and washed with 50 ml of acetonitrile twice. After drying, 44.52 g of perindopril erbumine was obtained as a white powder. Yield: 81% Example 3 (2S, 3aS, 7aS) -1-. { 2- [(1-ethoxycarbonyl) - (S) -butylamino] - (S) -propionyl} -octa idroindole-2-carboxylate of tert-butylamine (Perindopril Erbumine) To a cooled suspension of 5 g of N-. { 1- (S) ethoxycarbonylbutyl} -1- (S) -alanine in 71 ml of dichloromethane, 4.47 g of N, '-carbonyldiimidazole were added. The mixture was cooled to 0 ° C and stirred for 1 hour. 5.05 g of (2S, 3aS, 7aS) -2-carboxy-octahydroindole were added at -5 ° C to the above solution and the mixture was stirred at -5 ° C for 1 hour. The dichloromethane was evaporated and 71 ml of water was added to the aqueous phase followed by the addition of 11.6 ml of 6N hydrochloric acid. The aqueous solution was saturated with sodium chloride and extracted with 120 ml of dichloromethane. The solvent was evaporated. The resulting oil was dissolved in 80 ml of ethyl acetate. 1.78 g of tert-butylamine was added while stirring at room temperature. The mixture was heated to aid the solution to then cool to 20 ° C. The resulting precipitate was filtered and washed with ethyl acetate. 80% yield, purity of <99% It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

Having described the invention as above, s claims as property contained in the following claims: 1. A process for the preparation of a compound of formula (IV) or an ester or a salt thereof, characterized by comprising: 1) reacting a compound of formula (I) wherein Ra represents Ci-4 alkyl, ¾ represents Ci_4 alkyl and Rc represents Ci_6 alkyl with a compound of formula X2C = 0 (wherein each X independently represents a leaving group) to give a compound of formula (II) wherein Ra, Rb and c are as defined above and 2) reacting the compound of formula (II) with a compound of formula (III) wherein Ra represents hydrogen or a protecting group. 2. A process according to claim 1, characterized in that Rd is hydrogen.
3. A process according to claim 1 or 2, characterized in that Ra is ethyl.
4. A process according to any of claims 1 to 3, characterized in that Rb is methyl.
5. A process according to any of claims 1 to 4, characterized in that Re is propyl.
6. A process according to any of claims 1 to 5, characterized in that it comprises 1) reacting a compound of formula (A) with a compound of formula X 2 C = 0 (wherein each X independently represents a leaving group) to give a compound of formula (B) 2) reacting the compound of formula (B) with the compound of formula (C)
7. A process according to claim 6, characterized in that it further comprises reacting a compound of formula (C) with terbutylamine.
8. A compound of formula (II) characterized in that Ra represents Cx-4 alkyl, Rb represents Ci_4 alkyl and Rc represents Ci_s alkyl.
9. A process for the preparation of a compound of formula (I) characterized in that it comprises reacting a compound of formula (V) and (VI) (V) (I) wherein Ra b and Rc are as defined above and Re, together with the oxygen atom to which it is attached forms a leaving group and hydrogenate the product thereof.